Summary There is a critical need for improved methods for both contraception and HIV prevention. Nearly half of all pregnancies in the U.S. are unintended, and globally there are >85 million unintended pregnancies and 2 million new HIV infections each year. Not surprisingly, unintended pregnancies occur most often in women who are non-users of contraception: many women are averse to using exogenous hormones due to real and perceived side effects, and frequently discontinue hormonal contraception. This underscores the need for a non-hormonal contraceptive method that does not require coitally-timed actions, nor daily intervention. We believe adding contraception to an HIV prevention method would also strongly improve user adherence, since few couples self-identify as at risk of HIV, while nearly all self-identify as at risk of pregnancy. Inspired by nature, where some infertile women express antibodies that bind surface antigens on sperm and block sperm penetration through their cervical mucus, we have investigated a fully human monoclonal antibody (mAb) that can quickly bind a unique antigen present only on the surface of human sperm; we refer to this mAb as human contraceptive antibody (HCA). Importantly, HCA agglutinated >90% of sperm within seconds in all 100 fresh semen samples tested from men spanning diverse demographics. A similiar mAb that binds rabbit sperm reduced egg fertilization by ~95% in the highly fertile rabbit model. Major strides have been made with discovering and testing broadly neutralizing mAb (bnAb) against HIV, including protection against vaginal HIV transmission. Indeed, members of our team led the first clinical trial of VRC01 delivered vaginally. To realize the vision of a mAb-based MPT product, the next step in our development is to (i) formulate mAb into a delivery system that maintains effective levels of mAb in the female reproductive tract, and (ii) further validate efficacy in large animal models. Thus, during Phase I of this Fast-Track application, we will formulate sustained release polymeric capsules encapsulating a cocktail of mAbs (HCA and VRC01+N6 for HIV prevention), and can be embedded into intravaginal rings (IVR). The goal is to demonstrate that loaded mAbs will remain sufficiently stable and active (neutralize/trap HIV and agglutinate/trap sperm) when exposed and released into human cervicovaginal secretions over a 35 day period. Pending successful completion of Phase I milestone, we will perform repeated low-dose vaginal SHIV challenges to confirm if mAb released from the engineered polymeric capsules can effectively reduce vaginal transmission. If successful, our proposed work will strongly support clinical development of our combination contraceptive and HIV-prevention MPT-IVR that could address a major unmet need in the marketplace.